By K. Kayor. Teachers College.
On the other hand discount extra super avana 260 mg erectile dysfunction treatment pills, a drug with a high thera- peutic index has a wide margin of safety and poses less risk of toxic effects buy 260mg extra super avana fast delivery impotence vs infertile. Dose-response curve This graph shows the dose- response curve for two different 100 drugs extra super avana 260 mg low price erectile dysfunction drug approved to treat bph symptoms. As you can see buy generic extra super avana 260 mg erectile dysfunction treatment los angeles, at low C D doses of each drug, a dosage increase results in only a small increase in drug response (for example, from point A to point B for drug X). At higher doses, an Drug X Drug Y increase in dosage produces a 50 much greater response (from point B to point C). As the dosage continues to climb, however, an increase in dosage B produces very little increase in response (from point C to point A E D). When choosing a drug to treat a particular condition, health care providers consider not only the drug’s effectiveness but also other factors such as the type of therapy the patient will receive. Coinciding medical condi- a drug tions and personal lifestyle characteristics must be considered Because no two people when selecting drug therapy. Drug tolerance occurs when a patient develops a decreased • age response to a drug over time. The patient then requires larger dos- • cardiovascular es to produce the same response. Drug interactions Drug interactions can occur between drugs or between drugs and foods. They can interfere with the results of a laboratory test or produce physical or chemical incompatibilities. The more drugs a patient receives, the greater the chances that a drug interaction Memory will occur. The effects are equivalent to the sum of either drug’s effects if it were administered alone in higher doses. Giving two drugs together, such as two analgesics (pain reliev- ers), has several potential advantages: lower doses of each drug, decreased probability of adverse reactions, and greater pain con- trol than from one drug given alone (most likely because of differ- ent mechanisms of action). There’s a decreased risk of adverse ef- fects when giving two drugs for the same condition because the patient is given lower doses of each drug—the higher the dose, the greater the risk of adverse effects. A synergistic situation A synergistic effect, also called potentiation, occurs when two drugs that produce the same effect are given together and one drug potentiates (enhances the effect of) the other drug. Fighting it out An antagonistic effect occurs when the combined response of two drugs is less than the response produced by either drug alone. An absorbing problem Two drugs given together can change the absorption of one or both of the drugs: • Drugs that change the acidity of the stomach can affect the abil- ity of another drug to dissolve in the stomach. Sometimes, an absorption-related drug interaction can be avoided by administering the drugs at least 2 hours apart. Bound and determined After a drug is absorbed, the blood distributes it throughout the body as a free drug or one that’s bound to plasma protein. When two drugs are given together, they can compete for protein-binding sites, leading to an increase in the effects of one drug as that drug is displaced from the protein and becomes a free, unbound drug. Toxic waste Toxic drug levels can occur when a drug’s metabolism and excre- tion are inhibited by another drug. Some drugs stimulate enzyme production, increasing metabol- ic rates and the demand for vitamins that are enzyme cofactors (which must unite with the enzyme in order for the enzyme to function). For instance, when food that contains Vitamin K (such as green, leafy vegeta- bles) is eaten by a person taking warfarin, the drug’s anticoagula- tion properties are decreased and blood clots may form. Grapefruit can inhibit the metabolism of certain medications, resulting in toxic blood levels; examples include fexofenadine, albendazole, and atorvastatin. Because of all the interactions food can have with drug metabolism, being aware of drug interactions is essential. Adverse drug reactions A drug’s desired effect is called the expected therapeutic re- sponse. An adverse drug reaction (also called a side effect or ad- verse effect), on the other hand, is a harmful, undesirable re- sponse. Adverse drug reactions can range from mild ones that dis- appear when the drug is discontinued to debilitating diseases that become chronic. Adverse reactions can appear shortly after start- ing a new medication but may become less severe with time. Dosage dilemma Adverse drug reactions can be classified as dose-related or patient sensitivity–related. Most adverse drug reactions result from the known pharmacologic effects of a drug and are typically dose- related. Dose-related reactions include: • secondary effects • hypersusceptibility • overdose • iatrogenic effects. For example, morphine used for pain control can lead to two extreme sensitivity to undesirable secondary effects: constipation and respiratory de- a drug. Diphenhydramine used as an antihistamine produces se- dation as a secondary effect and is sometimes used as a sleep aid. Enhanced action A patient can be hypersusceptible to the pharmacologic actions of a drug. Such a patient experiences an excessive therapeutic re- sponse or secondary effects even when given the usual therapeu- tic dose. Hypersusceptibility typically results from altered pharmacoki- netics (absorption, metabolism, and excretion), which leads to higher-than-expected blood concentration levels. Increased recep- tor sensitivity also can increase the patient’s response to therapeu- tic or adverse effects. A toxic drug reaction can occur when an excessive dose is taken, either intentionally or by accident. The result is an exaggerated re- sponse to the drug that can lead to transient changes or more seri- ous reactions, such as respiratory depression, cardiovascular col- lapse, and even death. To avoid toxic reactions, chronically ill or elderly patients often receive lower drug doses. Iatrogenic issues Some adverse drug reactions, known as iatrogenic effects, can mimic pathologic disorders. Other examples of iatrogenic ef- fects include induced asthma with propranolol, induced nephritis with methicillin, and induced deafness with gentamicin. You’re so sensitive Patient sensitivity–related adverse reactions aren’t as common as dose-related reactions. Sensitivity-related reactions result from a patient’s unusual and extreme sensitivity to a drug. These adverse reactions arise from a unique tissue response rather than from an exaggerated pharmacologic action. Extreme patient sensitivity can occur as a drug allergy or an idiosyncratic response.
The elevated levels are due to hepatic injury generic extra super avana 260 mg without a prescription losartan causes erectile dysfunction, and (5) Drugs that interfere with the assay are extra super avana 260mg on-line erectile dysfunction 40, namely : (a) phenylazopyridine hydrochloride—a coloured drug generic extra super avana 260mg with mastercard impotence icd 10, (b) azo-compound forming medicinals cheap 260mg extra super avana with visa psychological reasons for erectile dysfunction causes, and (c) degradation product of novobiocin. Cholesterol Cholesterol interacts with glacial acetic acid and acetic anhydride to result into the formation of a coloured product whose absorption is measured at 630 nm and this is found to be directly proportional to the level of cholesterol present in the serum. Profile of Cholesterol Levels (1) Normal total cholesterol level is 200 mg per 100 ml, (2) Increased cholesterol levels in serum are found in patients suffering from chronic hepatitis, atherosclerosis (deposit of fat in arteries of heart) and hypothyroidism, (3) Decreased cholesterol levels in serum is indicative of liver ailment and hyperthyroidism, (4) Corticosteroids (i. Theory : All colorimetric enzymatic assays essentially involve the measurement of the activity of an ezyme under the following two circumstances, namely : (a) When substrate is in large excess, and (b) When enzyme concentration is in large excess. Therefore, with a view to obtaining the best results, the two experimental parameters, namely : the temperature (constant-temperature-water-bath) and the time (phaser) should always be kept constant in order that the rate of reaction, as determined by the amount of product formed, specially designates the activity of the enzyme under assay, and devoid of the influence of any other variables on the reaction rate. Enzyme Concentration in Large Excess In order to analyze the quantity of substrate (S) present in a biological sample glucose oxidase is added in excess of the actual amount needed for the complete conversion of all the substrate to product ; and to achieve this object the reaction is allowed to run for a fairly long duration (i. Assay Methods A few typical examples of colorimetric assay of enzyme levels will be discussed briefly hereunder : 2. The resulting amount of p-nitrophenolate ion is estimated by the help of an usual standard curve employing known concentrations of p-nitrophenolate prepared from p-nitrophenol. Bessey-Lowry Activity : One unit of activity may be defined as the amount of enzyme present in 1 millilitre of serum that liberates 1µ mol of p-nitrophenol (0. Elimination of Interference due to Coloured Drugs p-Nitrophenol is colourless, whereas the phenolate ion under basic conditions is yellow in appeanace. Therefore, the elimination of interference due to coloured drugs present in the serum is accomplished effectively by first, measuring the absorbance of the serum under basic conditions, and secondly, under acidic conditions. Interference due to Bilirubin Bilirubin is eliminated by dializing the incubated p-nitrophenolate ion (at pH 10. Some typical examples are, namely : amitriptyline, chloropropamide, erythromycin, phenylbutazone, sulpha-drugs and tetracyclines. The one with water serves as a reagent blank and is always needed per set of unknowns. Now, put the two tubes for incubation for exactly 30 minutes period, (iii) Enzyme activity is arrested by adding 10. Remove them from the water-bath and mix the contents thoroughly, (iv) Read out the absorbance of the unknown tube at 410 nm against the ‘reagent blank’ tube, (v) Transfer the contents from the cuvets to the respective test-tubes and add 0. This operation removes the colour developed due top-nitrophenol, (vi) Again read out the absorbance of the serum sample against the reagent blank tube at 410 nm. This gives the colour due to the serum itself, (vii) Now, the corrected reading is achieved by subtracting the reading obtained in step (vi) from the reading in step (v). The alkaline-phosphatase activity of the serum as Bessey-Lowery units is obtained from the calibration-curve step (i). Under these experimental parameters, we have : 1 Bessey-Lowry Unit = 5 × 10–8 mol of p-Nitrophenolate anion. Thus, one unit of phosphatase activity liberated 1 µ mol of p-nitrophenol (l µ mol = 0. Note : In case, a value more than 10 Bessey-Lowry Units is obtained, it is always advisable to repeat the process either with a smaller volume of serum or a shorter incubation period, and then finally adjust the calculations accordingly. In a kinetic enzymatic assay a unit of enzyme activity is defined as ‘the quantity of enzyme that brings about a certain absorbance increase in 30 seconds or 1 minute at a fixed temperature (for instance 25 ± 0. In this particular instance lactic acid available in an excess to ensure that the increase in pyruvic acid is linear with time, i. Hence, if the temperature (experimental) is higher or lower than that used to define a unit of activity, a definite correction factor should be applied as per Table 2. Carefully record the absorbance exactly at intervals of 30 seconds for 2 to 3 minutes. In case, the absorbance happens to rise very rapidly, repeat step 3 by diluting 0. A hapten (or haptene) is a small molecule that represents the portion of an antigenic molecule or complex which determines its immunologic specificity, for instance : cortisol ; whereas an antibody is a relatively large protein that is specific for certain haptens. An antibody is generated by binding the hapten to a protein, resulting into the formation of an antigen that specifically stimulates the immune system to produce antibodies specific for the hapten. The assays that utilize protein instead of antibody are normally termed as competitive protein bind- ing assays. As an antibody is also a protein, therefore, a radioimmunoassay may be looked upon as a type of competitive protein binding assay. Theory : Generally, a radioimmunoassay makes use of a radioactive hapten and subsequently the percent of radioactivity bound to the antibody is measured. The radioactivity is determined by the help of a Geiger- Müller Counter or Geiger-Counter or G-M Tube and sometime by a Scintillation Counter. First of all, a ‘Standard Curve’ or a ‘Calibration Curve’ is plotted between the reciprocal value (i. Thus, the amount of hapten present in the unknown sample is measured from the plotted calibration curve conveniently. The radioimmunoassay is based on the evolved competition between the combination of radioactive (Ha+) and nonradioactive (Ha) hapten to the antibody as represented below : Let us assume that the binding constants for Ha+ and Ha are equal ; now, for a fixed quantity of Ha+ but an increased concentration of Ha. In actual practice, however, the use of Tritium (H3) or Carbon-14 (C14), which helps to render the Ha radioactive, ulti- mately maintains the equality of these binding constants, namely : K + and K. It also confirms that the Ha Ha * The amount of enzyme that catalyzes the conversion of l µ mol of lactate per minute. Salient Features of Radioimmunoassays (1) They belong to a class of extremely sensitive methods of analysis, (2) Sample required for assay is usually very small e. Cortisol (In Plasma) Theory : Cortisol (or hydrocortisone) was introduced in the year 1951, for the treatment of rheumatoid arthritis. It also exerts widespread effects on carbohydrates, lipid and protein synthesis (or anabolism). The cardinal side effects such as excessive potassium excretion and sodium retention, enhanced gastric acidity, oedema, psychosis and negative nitogen balance are some of the exaggerated manifestations of the normal metabolite functions of cortisol. Most importantly, the determination of cortisol levels is considered useful in the diagnosis and treatment of various ailments, namely : Addison’s Disease i. In the actual radioimmunoassay the cortisol present in the extract competes with Cortisol-H3 (i. Now, the free cortisol is quantitatively removed by adsorption on dextran-coated charcoal from the one bound to the transcortin. Finally, the bound radioactivity (due to Cortisol-H3) is measured which is then employed to calculate exactly the amount of cortisol present in the sample by the help of a Standard Curve (or Calibration Curve). Procedure : The various steps to be followed sequentially for the assay of cortisol in plasma are as follows : (1) The cortisol is usually extracted from the samples drawn from the patients, as follows : Place 100µl of plasma in each of two tubes and add 2. Set tubes 1 and 2 aside until Step-13, Step-6 From this point onwards the various tubes are treated as follows : Step-7 Incubate tubes 3 through 18 and all patient sample tubes in a pre-set constant temperature water-bath at 45°C for exactly 5 minutes, Step-8 Immediately after Step-7 incubate tubes 3 through 18 and all patient tubes in an ice-water bath (0 to 4°C) for 30 minutes. Shake the rack several times at short-intervals to ensure that the tubes attain 0-4°C rapidly, Step-9 Quickly add 0.
Chaperones bring about therapeutic eﬀect downstream of translation by ‘protecting’ their target proteins (e buy extra super avana 260 mg without a prescription impotence of organic organ. Amicus Therapeutics discount 260 mg extra super avana with mastercard erectile dysfunction doctor in chennai, arguably the company with the broadest portfolio of small molecule pharmacological chaperones cheap 260 mg extra super avana otc medical erectile dysfunction pump, is leveraging its technology platform to develop orally bioavailable therapies to address lysosomal storage disorders including Fabry 260 mg extra super avana fast delivery impotence leaflets, Gaucher and Pompe diseases. More so, orphan drug reim- bursement, by private or public payer, has traditionally been generous, aﬀording most patients in the small orphan disease communities with access to medicines, which are oen life-saving and/or provide signicant quality of life attributes. Some of these payer management tools, approaches and tactics include the use of restrictive tiers, prior authorisation, step therapy, increased patient coinsurance and/or co-payment, genetic testing (i. Creative risk-sharing schemes, in addition to traditional patient access programmes and manufacturer discounts, are increasingly playing an important role in the provision of orphan drugs to patients. This concept is taken further with performance-based risk-sharing agreements for ultra-orphan therapies, where price reductions can be entertained or negoti- ated if clinical outcomes are suboptimal or not compelling, which provides an approach to address the uncertainty regarding the long-term eﬀectiveness of costly ultra-orphan drugs. In summary, the key dimensions of commercialisation success around which companies must diﬀerentiate in order to win in the orphan drug market include understanding and exploiting orphan disease market fundamentals (e. There are two key evaluations or reports that have investigated this topic – the Drug Discovery Today article ‘Orphan Drug Development: An Economically Viable Strategy For Biopharma R&D’ (published in 2012), and EvaluatePharma’s ‘Orphan Drug Report’ (published in 2013). This indicates that mean per-year economic values of the orphan and non-orphan drug cohorts were almost equal, which underscores the value-creation viability of orphan drugs. View Online 102 Chapter 4 overall pharmaceutical market (excluding generics), as outlined in Figure 4. A separate analysis, in the same report, demonstrated a statistically signicant greater trend for multi-indication orphan drugs to target initial approval in an orphan vs. When the development plans for individual orphan drugs are being created, the cost, complexity, challenges and high-risk nature of pharmaceutical R&D in general should not be underestimated. The current trends in the orphan drug product development arena provide some interesting themes and an inno- vation imperative for inuencing the evolution of the biopharmaceutical landscape – for orphan drug R&D specically, as well as continual stimula- tion of biopharmaceutical R&D in general. Orphan drug R&D will make important contributions to life sciences research, drug discovery and translational medicine, thereby enhancing therapeutic development approaches (e. Indeed, orphan drug R&D experiences will help to advance the development and use of personalised/stratied medicine approaches and targeted medicines. Orphan drug R&D also has a key role in evolving clinical development paradigms (e. It will be interesting to see the extent to which ‘real world trials’ are included as part of ongoing orphan drug development programme eﬀorts to expand clinical data sets and update the risk–benet prole of orphan drugs. The ‘real world trial’ paradigm, gathering eﬃcacy and safety data across countries where feasible, could help encourage greater use of progressive (not only conditional) regulatory approval approaches for orphan drugs, which could help address concerns regarding the paucity of clinical data available at the time of marketing authorisation. Awareness, education, outreach and marketing approaches, for consumers and prescribers, will also be inuenced by the degree to which orphan drugs embrace social media and community connectivity models. Merkel and Rare Diseases Clinical Research Network, Mol Genet Metab, 2009, 96,20–26. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 109 33. View Online Treating Rare Diseases: Business Model for Orphan Drug Development 111 76. Patient support groups, voluntary health organisations and disease advocacy organisations are just a few of the names by which advocacy and support for rare conditions is known. These organisations run the gamut from simple support for people aﬀected by a condition to full-blown research entities that rival some pharmaceutical companies in nancing and capacity. When specically considering drug development for rare diseases, it is more likely that the organisation lies at the research entity end of the spectrum. In determining what phrase to use to describe these entities, it should also be noted that there is a growing distaste in both umbrella bodies comprised of these organisations as well as among the individuals aﬀected by rare conditions for the term ‘patient’. Much of the lives of these individuals and their families are spent living with a chronic condition, and not in the care of a physician. The word ‘patient’ connotes the less than empowering position of being in the doctor–patient dyad and not in a position of power and participation. Biomedical research, and particularly drug development, lying as it does on the far end of the translational spectrum, requires participation of the individuals, families and communities it will benet. It would perhaps be more precise to say ‘disease research organisations’, but that would limit the discussion unnecessarily, because a substantial part of the acceleration of drug development in rare diseases comes from activity other than direct scientic research. Their participation is uneven and fragmented, thus not easily discernable or measured, although there are certainly extraordinary excep- tions. These organisations span the continuum from providing simple support for aﬀected individuals and families, to creating and operating full-blown for-prot pharmaceutical companies. However, as described in detail in other chapters of this book, there is little incentive for these companies to invest in diseases with low or negligible commercial potential, because this business model is driven by very ambitious revenue and quarterly prot goals. Looking ahead and in the context of a quite generalised economic crisis, the commercial attractiveness of developing drugs for small disease populations is becoming increasingly ‘uncertain’. Indeed six-digit treatment costs per year are less and less likely to remain bearable for strangled health care systems and the ethical pressure of providing access to health care to those suﬀering from rare and oen debilitating diseases is putting strong pressure on treatment pricing. As described elsewhere, it takes up to 18 years, on average, for a drug to move from discovery to commercialisation. Only ve in 5000 compounds that enter preclinical testing make it to human testing, and only one of those ve is ever approved for use. This is not an imaginable or acceptable failure rate for those aﬀected by disease. Estimates for R&D costs for a single new drug (taking into account failed projects) can now range between $800 million to $1. Because successes are scarce, failures are the norm, and costs continue to rise, the pharmaceutical industry is scrambling for answers to reduce the inherent risks of this endeavour and is attempting to shorten the timelines of the R&D process, while minimising attrition through stringent quality controls and de-risking strategies at all levels. Despite all these eﬀorts, the uncertainties and the nancial risks remain high, translating into enormous pressure on pharmaceutical companies. In the last 5 years, most large pharmaceutical companies have cut their staﬀs substantially, most notably within the research workforce, and now focus principally on only the lowest risk and highest prevalence targets and diseases with proven or plausible commercial potential. That is no longer the major concern – pharmaceutical and biotech companies have begun to see rare diseases as a solution to their woefully stressed business models. They are clearly aware that this is a lucrative business and will draw a substantial audience. Thus registration fees of more than $1000 per attendee are typical, and there is no lack of participation. There has been a great deal of discourse about how to actually impact the translational research system to increase its eﬀectiveness. Many pharmaceutical companies are opening rare disease therapeutic development divisions, hop- ing to capitalise on the generally high prices these drugs can garner, as well as attempting to discover new models to sustain and advance the industry. Mindful of the fact that only about 5% of all rare conditions have treatments, and aware that organisations such as the International Rare Disease Research Consortium16 declare an international goal of 200 new interven- tions by 2020, there is no doubt that a new model or models are critical.
The monomeric anhydride bonds have extreme reactivity toward water and undergo hydrolysis to generate the dicarboxylic acids (27) buy 260mg extra super avana overnight delivery statistics of erectile dysfunction in us. Although hydrolysis is catalyzed by both acid and base order extra super avana 260mg on line jack3d causes erectile dysfunction, an increase in pH enhances the rate of hydrolytic degradation buy discount extra super avana 260 mg on line erectile dysfunction diabetes medication. At low pH buy extra super avana 260 mg with amex erectile dysfunction treatment cincinnati, oligomeric products formed at the surface of the matrix have poor solubility; this hinders the degradation of the core. The degradation rate of these polymers can be either accelerated by the incorporation of sebacic acid, a relatively more water-soluble aliphatic comonomer than carboxyphe- noxy propane, into the polymer or reduced by increasing the methylene groups or long-chain fatty acid terminal such as stearic acid into the polymer backbone, thereby increasing the monomeric chain length, its hydrophobicity, and the ero- sion rate (28,29). The branching of poly(sebacic acid) with either 1,3,5-tricarboxylic acid or low molecular weight poly(acrylic acid) results in an increased erosion rate (30). It is also known that aliphatic anhydrides and their copolymers undergo a ﬁrst-order, self-depolymerization reaction, under anhydrous conditions both in solid state and in solution (31). The rate of depolymerization is found to increase with temperature and the polarity of the solvent. Studies on copolymers of several polyanhydride families have shown that varying comonomer ratios produce ero- sion proﬁles ranging from days to years (32). Biocompatibility During biocompatibility testing of linear aliphatic polyanhydrides in rats, histopathological examination of tissue specimens that were in direct contact with the polymer device showed mild inﬂammation, but macroscopically, no swelling or pathological signs were observed (27). In another set of compatibility studies, these polyanhydrides were shown to be nontoxic, nonmutagenic, and nonteratogenic (36). A rabbit cornea bioassay indicated the absence of an inﬂammatory response with implanted polyanhydrides (37). In a rabbit animal model, blank polyanhy- dride particles did not elicit any inﬂammatory response; however, when a tumor angiogenic factor was incorporated within the polymer matrix, it resulted in a sig- niﬁcant vascularization response, further proving the innocence of the polymer by itself (38,39). When tested in rats, polyanhydrides based on ricinoleic acid did not show any signs of tissue necrosis 21 days postimplantation, while only minimal Polymeric Nanoparticles for Small-Molecule Drugs 21 subacute inﬂammation and mild ﬁbrosis were noted (40). Clinical trials in humans with a polyanhydride dosage form, Gliadel r , produced no systemic or central tox- icity, thus demonstrating its biocompatibility and acceptability for human use (41). Polyorthoesters Biodegradation Although polyorthoesters are hydrophobic in nature, their orthoester linkage is acid sensitive and highly unstable in the presence of water. The primary mechanism by which these polymers degrade is hydrolysis, and, depending on the reactants used during the polymer synthesis, the degradation products are a diol, a triol, or a mix- ture of diols and carboxylic acid. This in situ production of acid further catalyzes the breakdown of these orthoester linkages, thus resulting in the bulk erosion of the matrix. The rate of this acid-catalyzed hydrolysis of the pH-sensitive linkage can be controlled by incorporating either acidic or basic salts into the polymer matrix (42). This was demonstrated in experiments with 5-ﬂuorouracil-embedded poly- orthoester nanoparticles – when suberic acid was incorporated as an additive, the acidic excipient accelerated the rate of hydrolysis and caused signiﬁcantly faster release of the drug (43). Alternatively, when the interior of the matrix is buffered with basic salts, the generated acid is neutralized and hydrolysis can be retarded. In this way, they stabilize the bulk of the matrix but allow the drug to escape from the surface region, thus converting the system into a surface-eroding polymer type. For example, the release of tetracycline from a polyorthoester matrix was found to be extremely rapid; however, the addition of 0. Certain poly- orthoesters containing glycolide sequences exist that undergo hydrolytic degrada- tion by autocatalysis without the use of any excipients (45). The control over the erosion rate can also be extended by altering the amount of catalyst, phthalic anhy- dride, present in the polymer (46). The var- ious parameters that can be externally controlled to yield nanoparticles of desired physicochemical characteristics, drug entrapment efﬁciency, and drug release rate properties include the nature and solubility of the drug to be encapsulated, polymer type and concentration, its molecular weight, composition of the copolymers, drug- loading concentrations, type and volume of the organic solvent, the water phase volume, pH, temperature, concentration, types of surfactants, and the mechanical speed of agitation. In vitro and in vivo responses from the nanoparticles are inﬂu- enced by their various properties, such as the particle size and size distribution, sur- face morphology, porosity, surface chemistry, surface adhesion, zeta-potential, drug 22 D’Mello et al. Conventionally, nanoparticles can be prepared either by dispersion of the preformed polymers or by the in situ polymerization of the monomers. Laboratory-Scale Production of Nanoparticles Phase Separation in Aqueous System The use of coacervation technique to develop polyester microspheres was ﬁrst reported by Fong in 1979 (48) and modiﬁcations of the same are used today for the production of nanoparticles. This technique depends on the precipitation of the drug-entrapping polymer either by the addition of a third compound to the poly- mer solution or by some other physical means. The point has to be reached where two liquid phases are formed, the polymer-rich coacervate and the supernatant liquid phase, which is depleted in the polymer. Brieﬂy, two steps are involved in the process: (i) the formation of liquid droplets of the polymer from the complete solution phase, which depends on the solubility parameters of the polymer, and (ii) subsequent hardening of the polymer droplets due to extraction or evaporation of the polymer solvent. A number of organic solvents, such as dichloromethane, isopropanol, and heptanes, have been used as solvent, coacervating agent, and hardening agent. If a drug is initially dispersed in the polymer solution, it can be coated by the coacervate. Phase separation could occur as a result of changes in pH (49) or counterions (50), or as a result of the aqueous phase acting as a nonsolvent for the polymer. Both hydrophilic and hydrophobic drugs can be entrapped by this principle, albeit with different drug-entrapment efﬁciencies. For example, hydrophilic drugs can be solubilized in water and this aqueous phase can be added to an organic solution of the polymer (w/o emulsion) (51), whereas lipophilic drugs can be dissolved/dispersed in the polymer solution. Hydrophilic drug–entrapment efﬁciency decreases signiﬁcantly if a large volume of water is used in the process, or water is used as a coacervating agent. Various process variables such as the aqueous phase/organic phase volume ratio, stirring rate, addition rate of the nonsolvent, polymer concentration, polymer solvent/nonsolvent ratio, and viscosity of the nonsolvent affect the characteristics of the nanoparticles such as morphology, internal porosity, and the size distribution (52,53). The surface porosity of particles normally depends on the solvent extraction process, whereas the shape is normally spherical. The main advantage of phase-separation method is that it protects active drugs from partitioning out into the dispersed phase. However, the residual solvent content is a major concern, especially when organic solvents are used as the hardening agent (54). Emulsion-Solvent Evaporation/Extraction In this method, the polymer is ﬁrst dissolved in a water-immiscible, volatile, organic solvent such as chloroform, dichloromethane, or ethyl acetate (55). To harden the nanoemulsion droplets into solid nanoparticles, the organic solvent is evapo- rated or extracted from the system after it diffuses into the external aqueous phase. For the removal of solvent, the stirring process may be continued for several hours at Polymeric Nanoparticles for Small-Molecule Drugs 23 high-temperature/low-pressure conditions; a quicker option to harden the parti- cles may be to pour the emulsion into water, causing the solvent to phase toward the surfactants in the interface and eventually diffuse out into the aqueous phase. Normally, the rate of solvent extraction or evaporation has signiﬁcant effects on the porosity of the nanoparticles, which, in turn, signiﬁcantly affects the drug release from the nanoparticles. Since the solvent extraction is normally faster than the evap- oration rate (the latter depends on the boiling point of the solvent), the resultant porosity of the nanoparticle matrix prepared by the solvent extraction method is usually greater than the nanoparticles prepared by using the evaporation process (56). Nanoparticles may be harvested by centrifugation or ﬁltration, washed, and freeze-dried to produce free-ﬂowing nanoparticles. One of the challenges encoun- tered in this method is the poor entrapment and burst release effect of moderately – water-soluble and hydrophilic drugs.
Rem ark The addition of ethanol is not essential because it reduces the viscosity purchase extra super avana 260 mg amex causes of erectile dysfunction young males. Influence of the com pression force on the tablet properties (300 m g tablet w eight) com pression force Property 7 kN 15 kN 22 kN Hardness 45 N 110 N 160 N Disintegration 1 m in 2 – 3 m in 3 – 4 m in Friability 0 buy 260mg extra super avana overnight delivery erectile dysfunction pills cost. M anufacturing of the spray Fill the solution into spray cans with the necessary quantity of propellant (e generic extra super avana 260 mg with mastercard erectile dysfunction drugs non prescription. Pass the blended m aterial through a wide sieve hole disk com bined with a m outh hole disk cheap extra super avana 260mg fast delivery erectile dysfunction tucson. Pass the blend four tim es through a three-roller m ill and let dry over night at room tem perature. Adm inistration as preventive desinfectant Dilute about 3 m l of the concentrate with 1 l of water. Fill the aerosol cans with 90 parts of this solution and 10 parts of propane + butane (1+3). Chem ical stability (14 days, 52 °C) The content of available iodine dropped to 98%. M anufacturing Dissolve Lutrol E 4000 in the hot m ixture of glycerol and water and add the glucose warm ed to 60 – 80 °C. Rem ark A sim ilar form ulation using sucrose instead of glucose is m entioned in the European Patent 0258761 (Kowa). W hen a hom ogeneous suspension has been obtained cast the sticks in preform ed m oulds. Chem ical Stability The obtained solutions showed no loss of iodine after the storage of 15 days at 60 °C. Stability (52 °C, 14 days) The cream is physically stable and shows no loss of iodine. M anufacturing Dissolve potassium iodide in water, warm up to 40 °C and dissolve xylitol. Chem ical stability After storage of 15 hours at 80 °C a loss on iodine of about 7% has been determ ined. Properties of the solutions Brown, clear solutions having a certain viscosity and a pH of 3 – 4. Chem ical stability In the stress test (14 days, 52 °C) the loss of available iodine was about 12 %. Properties of the solutions Brown clear solutions having a low viscosity and pH of about 4. Chem ical stability After the storage at 52 °C during 14 days the loss of available iodine was 11. Stability (14 days, 52 °C) The content of available iodine dropped only to 99% and the pH to 3. Properties of the solution Brown, clear solution having a low viscosity and a pH of about 4. Chem ical stability In a stress test (14 days/52 °C) and at room tem perature (one year) no loss of available Iodine were m easured. Chem ical stability In a stress test (14 days/52 °C) and at room tem perature (one year) no loss of available Iodine were m easured. Chem ical and physical stability In a stress test (15 hours at 80 °C) the loss of iodine was 13. M anufacturing (Direct com pression) M ix all com ponents, pass through a sieve and press with low com pres- sion force. Suspend the pigm ents and talc in 216 m l of water and pass this m ixture through a colloid m ill. M anufacturing A 500-g sam ple of this suspension was passed through a disk m ill and sprayed under the following conditions: Sugar-coating pan Spray gun.................................. Suspend the pigm ents and talc in 168 m l of water and pass this m ixture through a colloid m ill. M anufacturing of the coating suspension Dissolve shellac and sorbitane oleate in the warm solvent and then Kollidon and cetyl alcohol. Rem ark If the flowability of the tabletting m ixture is not sufficient about 1% Aerosil 200  could be added. M anufacturing (Direct com pression) Dry saccharin sodium and tartaric acid 1 hour at 100°C. M anufacturing (Direct com pression) M ix all com ponents intensively, pass through a 0. Properties of the granules – Free flowing white granules; – 98% coarser than 50 µm ; – Easily dispersible in cold water without any physical separation during 30 m in. Adm inistration Take the content of one sachet (1 g = 60 m g sim ethicone or 2 g = 120 m g sim ethicone) as powder or disperse the recom m ended am ount (e. Rem ark If the content uniform ity does not m eet the requirem ents it would be recom m ended to prepare a prem ix of the active ingredient with a sm all part of the Ludipress or with lactose m onohydrate before m ixing with the other com ponents of the form ulation. M anufacturing (Direct com pression) M ix all com ponents, pass through a sieve and press with m edium com pression force. M anufacturing (Accela Cota) Spray the solution onto the warm tablet cores (30 – 40 °C) for few m inu- tes before to continue with the aqueous m ain coating procedure. M anufacturing of the coating suspension Dissolve the sucrose in the hot water, than m ix with glycerol, dissolve Kollidon 30 and suspend the other com ponents. Coating procedure 4 kg of tablet cores with a weight of 420 m g were sprayed with 2. M anufacturing of the coating suspensions Dissolve Kollidon, Polysorbate or Crem ophor and sucrose in the water and suspend the other com ponents in this solution. Rem ark The polishing can be done by m eans of a solution of beeswax or poly- ethylene glycol 6000. It showed som e sedim entation after 7 days but the redispersibility was very easy. Rem ark To prevent of discolouration of Kollidon in the solution during storage 0. M anufacturing Disolve sulfadoxine and trim ethoprim in Soluphor P, add the water, and set to pH 8. Properties of the solution A clear, colourless solution of low viscosity was obtained. Physical stability No change of the clarity after 2 weeks stored at 6 °C and at 20 – 25 °C. Preparation of the adm inistration form Shake 55 g of the powder with 100 m l of water until a hom ogeneous suspension is obtained. Properties of the obtained suspension No sedim entation during m ore than 24 hours. M anufacturing Dissolve Kollidon, parabene, sodium sulfite (or cysteine) in the m ixture of water und propylene glycol, heat, add the active ingredients and stir until they are dissolved. M anufacturing Dissolve Kollidon and sulfathiazole at 70 °C in water and cool slowly to room tem perature. M anufacturing Dissolve Kollidon 25 and Sulfathiazole at 70 °C in water and cool slowly to room tem perature. Rem ark If the content uniform ity does not m eet the requirem ents it would be recom m ended to prepare a prem ix of the active ingredient with a sm all part of the Ludipress or with lactose m onohydrate before m ixing with the other com ponents of the form ulation.
If the goods on test by the laboratory are found to be of standard quality and are labelled as prescribed buy 260 mg extra super avana does gnc sell erectile dysfunction pills, they may be released order extra super avana 260mg fast delivery erectile dysfunction causes depression. If the goods buy extra super avana 260mg amex erectile dysfunction muse, on test cheap extra super avana 260mg with visa impotence news, are declared to be not of standard quality, the Customs Commissioner is informed about this along with 2 copies of the test Report. The proforma of the Communication for action under Rule 41(1) used is given in Annexure: P-7, intimation about such imports are made to the Deputy Drugs Controller (India) with copies to the other Port Offices, the proforma used for such communication is given in Annexure: P-8. On the basis of the advice of the Port Officers the Customs will issue a show Cause memo to the firm concerned. On the basis of the party‘s reply the case will be finally adjudicated after ascertaining views of the Port Officers. In case the importers appeal for a retest by submitting sufficient evidence like manufacturer‘s protocols of test on the items in question, the case should be referred to the Deputy Drugs Controller (India) for orders along with comments of the Port Officer. If the Deputy Drugs Controller (India) so directs, a fresh sample shall be drawn, should be sent for retest to the laboratory. The orders passed by the Deputy 419 Drugs Controller (India) on the basis of such retest are final. Where the defect is such, that the importers undertake to recondition the goods up to the required standard, they must submit along with their appeal - a) The method that will be adopted for re-processing of Bulk Drugs. In case of grossly substandard / spurious / adulterated drugs, Commissioner of customs is to be informed stating that the import of these goods constitutes an offence u/s. In case of not of standard quality, other than those mentioned in point 6 above, the importers may be given the option to reship the goods to the country of origin if they so desire or forfeit them to the Central Government for destruction. For the import of non-notified diagnostic kits/reagents, only import license in Form-10 is required. The product label should comply with Rule 96 of Drugs and Cosmetics Rules including name and address of the manufacturer as stated in the Form-10, import license number. There are substances which are covered under the definition of the drug but are not used for medicinal purpose and are used in other industries like textile industries, chemical industries and food industries etc. After release of the goods, the same to be informed to the concerned State Drug Controller and the Zonal officer for post import check. The procedure to be followed in case of imports for personal use is detailed under Rule 36 of Drugs & Cosmetics Rule 1945. Other documents may be asked by the port officer to ensure the authenticity and quality of the cosmetics 4. Sample to be drawn at random and sent for test to Government appoved Testing Laboratories only. As regard to testing and follow up action is provided under Rule 131, the guidelines 424 and protocols to be followed is very much similar to the Drugs, only sections and rules to be changed. Simultaneously, the matter to be informed to the concerned State Drug Controller / Zonal Officer for the re- import check. Export permissions issued by the Deputy Drugs Controller for / fixed dose combinations / medicines beyond Schedule V limits / unapproved/approved new drugs/banned drugs under 26-A / without labels etc. Rule 94 violations – In case of export by loan licensee, the name and any address of manufacturer mentioned on the license may be acceptable. In case of neutral code, the consignment may be allowed as long as the identity of the manufacturer is ascertained with licence / code number available on the label. Aurvedic Drugs In case of export of ayurvedic drugs following documents are to be examined before release i) shipping bill, ii) Invoice, iii) packing list , iv) Mfg‘s test report of ayurvedic items for presence of heavy metals, Pb As, Sb, Hg within permissible limits (as per ayush guidline),specimen label/specimen sample, valid mfg. Licence with list of approved items labelling provision of ayurvedic drugs for export should comply with Rule 161A of D&C Rule. Subsequent to the above Notification, representations have been received from various Drug Manufacturers Associations requesting for exemption from registration requirements of the Drugs & Cosmetics Act for imports under the Advance Licensing Scheme. The requests have been considered and It has been decided that import of approved & unapproved drugs under the Advance Licensing Scheme will not be subjected to the Registration procedure and the imports will be permitted subject to the following conditions: i. Import license will only be given against an existing valid export order and to the extent raw material is required as per that order. A copy of the license would be endorsed to the Drug Controller and the concerned State Drug Controller. Any violation is punishable under the Foreign Trade Development and Regulation Act and the Customs Act. The Drug Controller could also make provisions for penalizing the Drug Manufacturing Units in terms of suspension or cancelling of his license. Export obligation will be fulfilled within a period of six months from the date of issuance of the license. However, if they make supplies to the domestic market, they will have to follow the formalities of registration as under the Drugs & Cosmetics Act. Representations have also been received regarding issuance of Form-10 under the Drugs & Cosmetics Act for manufacturers. It is clarified that Form -9 issued by the registered manufacturers should also be accepted for the purpose of issuing Form-10 license under the Drugs & Cosmetics Act. In addition as far as imports of drugs/raw materials for purposes of (i) clinical trials & (ii) for formulation development is concerned, it is clarified that exemption in such cases will be permitted on case to case basis. The exemption from registration procedure of the Drugs & Cosmetics Act will not only cover those drugs listed in Notification No. The Licensing Authority will make an endorsement on the licence that the exemption has been granted in terms of Policy Circular No. All importers making imports against advance licences, which have not been issued in terms of Policy Circular No. The export obligation period for the advance licences issued as per Policy Circular No. I) shall however be applicable for advance licences issued under Policy Circular 9 dated 30. Na M E Lan sh Shel Shel Batc i t N me din elf f f h t a o & ( g Lif Life Life wise l. That we shall arrange for inspection of the goods as soon as they arrive in the go-down and follow the instructions of representative of the O/o. Assistant Drugs Controller (I), with regard to drawing of samples for test, rectification of labelling defects etc. That we shall not dispose of the said goods without the consent of the Collector of Customs or any Officer on his behalf in writing. That we shall return the said goods in whole or in part as the Collector of Customs or any officer on his behalf may direct within ten days of receipt of a notice from the Collector of Customs or any officer on his behalf to return the goods. That we shall reship or surrender the said goods within two months of the receipt of any order to that effect from the Collector of Customs or any officer in his behalf. Any amount due under this bond may be recovered in the manner laid down in the subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode or recovery. The undertakings referred to above is given in view of rule 40 of the drugs and Cosmetics Rules 1945.